Topical insecticide

ABSTRACT

A topical insecticide is provided which can be safe to use and avoids many common deleterious side effects of conventional topical insecticides. In one preferred embodiment of the invention, the active ingredient of the insecticide formulation is an amine derivative, having a nitro-methylene group, a nitroamino group or a cyanoamino group, which can be formulated to have low toxicity and excellent insecticidal activity. One particularly suitable insecticide is 1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine (dinotefuran), an aldulticide that will kill adult fleas, dissolved in a solvent such as ethanol and/or DPM.

BACKGROUND OF INVENTION

The invention relates generally to insecticides and more particularly toa topical insecticide, such as one suitable to use on house pets such ascats and dogs.

The infestation of animals with fleas, ticks, flies and the like ishighly undesirable. Accordingly, it has become common to administer bothtopical and internal insecticides to livestock and pets. Topicalapplications can be desirable, in that many insecticides are acceptablysafe when used topically, but not when used internally.

Various topical insecticides have drawbacks. Some require a large volumeto be applied to the animal. This can cause considerable mess and canlead to an unpleasant smell. Also, when the animal is a house pet, thereis a further complication in that the insecticide should be safe forhuman contact. It should also not lead to staining of furniture,carpeting and the like. Finally, even if safe, topical insecticides forhouse pets should not be irritating or lead to rashes, hair loss orexhibit other unpleasant side effects.

Accordingly, it is desirable to provide an improved topical insecticide,which overcomes drawbacks of the prior art.

SUMMARY OF THE INVENTION

Generally speaking, in accordance with the invention, a topicalinsecticide is provided which can be safe to use and avoids many commondeleterious side effects of conventional topical insecticides. In onepreferred embodiment of the invention, the active ingredient of theinsecticide formulation is an amine derivative, having a nitro-methylenegroup, a nitroamino group or a cyanoamino group, which can be formulatedto have low toxicity and excellent insecticidal activity. Activeingredients of insecticides and their method of formation in accordancewith the preferred embodiments of the invention are discussed in U.S.Pat. Nos. 5,532,365 and 5,434,181, the contents of which areincorporated herein by reference. One particularly suitable insecticideis 1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine(dinotefuran). Dinotefuran is an aldulticide that will kill adult fleas.

In one preferred embodiment of the invention, the active portion of theinsecticide formulation comprises (tetrahydro-3-furanyl)methylaminederivatives of following formula (1).

Active ingredients and insecticides in accordance with preferredembodiments of the invention are generally available as crystals andsolids. Therefore, they need to be dissolved or otherwise put into aliquid form for use as topical spot products on animals.

In one aspect of the current invention, the compound is dissolved insolvent to a concentration range of 2-15%, more preferably 4-9% and mostpreferably about 5 to 8%, with 6% as a preferred example. Allpercentages, unless otherwise evident, are on a weight basis.

In one embodiment of the invention, the preferred solvent componentcomprises a mixture comprising water and an alcohol, preferably ethanol,at a concentration range of 50-80% ethanol, more preferably 65-75%ethanol and most preferably about 69-71% ethanol, with a preferredexample 70% ethanol. The remainder can be water. The insecticideformulation can include various additions to the ethanol/watercombination.

In another embodiment of the invention, the preferred solvent componentcomprises a mixture comprising water, ethanol and isopropanol, whereinthe final concentration of total alcohol range from 50-80% alcohol, morepreferably 65-75% alcohol and most preferably about 69-71% alcohol, witha preferred example 70% alcohol. The remainder can be water. Theconcentration of ethanol and isopropanol are 25-45% ethanol, 25-45%isopropanol, more preferably 30-40% ethanol, 30-40% isopropanol and mostpreferably 35% ethanol and 35% isopropanol.

In another embodiment of the invention, the preferred solvent comprisesa mixture comprising dipropyleneglycol monomethyl ether (DPM) and waterat a concentration range of about 30-70% DPM, more preferably about45-55% DPM and most preferably about 50% DPM/50% water mixture.

In yet another embodiment of the invention, the preferred solvent is amixture comprising water, ethanol and DPM at a concentration range of25-40% ethanol, 25-40% DPM, more preferably 30-35% ethanol, 30-35% DPMand most preferably equal volumes of each component (i.e., 33% ethanol,33% DPM and 33% water).

Accordingly, it is an object of the invention to provide an improvedtopical insecticide, which overcomes drawbacks of the prior art.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The novel (tetrahydro-3-furanyl)methylamine derivatives of the formula(1) have an excellent insecticidal activity even in the absence of apyridylmethyl group or a thiazolylmethyl group in their molecularstructure. According to the present invention, there are provided(tetrahydro-3-furanyl)methylamine derivatives represented by formula(1), where X₁, X₂, X₃, X₄, X₅, X₆ and X₇ represent each a hydrogen atomor an alkyl group having from 1 to 4 carbon atoms; R₁ represents ahydrogen atom, an alkyl group having from 1 to 5 carbon atoms, analkenyl group having 3 carbon atoms, a benzyl group, an alkoxyalkylgroup having from 2 to 4 carbon atoms (in its whole group), analkyloxycarbonyl group having from 1 to 3 carbon atoms, a phenoxycarbonyl group, an alkylcarbonyl group having from 1 to 6 carbon atoms,an alkenylcarbonyl group having from 2 to 3 carbon atoms, acycloalkylcarbonyl group having from 3 to 6 carbon atoms, a benzoylgroup, a benzoyl group substituted by alkyl group(s) having from 1 to 4carbon atoms, a benzoyl group substituted by halogen atom(s), a2-furanylcarbonyl group or an N,N-dimethylcarbamoyl group; R₂ representsa hydrogen atom, an amino group, a methyl group, an alkylamino grouphaving from 1 to 5 carbon atoms, a di-substituted alkylamino grouphaving from 2 to 5 carbon atoms (in its whole group), a 1-pyrrolidinylgroup, an alkenylamino group having 3 carbon atoms, an alkynylaminogroup having 3 carbon atoms, a methoxyamino group, an alkoxyalkylaminogroup having from 2 to 4 carbon atoms (in its whole group), a methylthiogroup or —N(Y₁)Y₂ (where Y₁ represents an alkyloxycarbonyl group havingfrom 1 to 3 carbon atoms, a phenoxycarbonyl group, an alkylcarbonylgroup having from 1 to 6 carbon atoms, an alkenylcarbonyl group havingfrom 2 to 3 carbon atoms, a cycloalkylcarbonyl group having from 3 to 6carbon atoms, a benzoyl group, a benzoyl group substituted by alkylgroup(s) having from 1 to 4 carbon atoms, a benzoyl group substituted byhalogen atom(s), a 2-furanylcarbonyl group, an N,N-dimethylcarbamoylgroup, a (tetrahydro-3-furanyl)methyl group or a benzyl group, and Y₂represents a hydrogen atom or an alkyl group having from 1 to 5 carbonatoms); and Z represents ═N—NO₂, ═CH—NO₂ or ═N—CN; insecticidescontaining the derivatives as an effective ingredient; and intermediatesfor producing the compounds of the formula (1) represented by a formula(2):

where X₁, X₂, X₃, X₄, X₅, X₆ and X₇ represent each a hydrogen atom or analkyl group having from 1 to 4 carbon atoms; R₁₀ represents an alkylgroup having from 1 to 5 carbon atoms or a benzyl group; and R₁₁represents an alkyl group having from 1 to 5 carbon atoms or a benzylgroup.

The novel (tetrahydro-3-furanyl)methylamine derivatives of the formula(1) and formula (2) according to the invention are excellent compoundshaving a high insecticidal power and broad insecticidal spectrum.Further, agricultural chemicals containing the novel(tetrahydro-3-furanyl)methylamine derivatives of the formula (1) and (2)according to the invention have outstanding characteristics asinsecticides and hence are useful.

Specific examples of the alkyl group for X₁, X₂, X₃, X₄, X₅, X₆ and X₇in the above formulae (1) and (2) include a methyl group, an ethylgroup, an n-propyl group, an iso-propyl group, a tert-butyl group, andthe like, preferably a methyl group.

Specific examples of the alkyl group for R₁ include a methyl group, anethyl group, an n-propyl group, an iso-propyl group, an n-butyl group,an iso-butyl group, a sec-butyl group, a tert-butyl group, an n-pentylgroup, and the like.

Specific examples of the alkenyl group for R₁ include a 1-propenylgroup, a 2-propenyl group, and the like.

Specific examples of the alkoxyalkyl group for R₁ include amethoxymethyl group, an ethoxymethyl group, an n-propoxymethyl group, aniso-propoxymethyl group, a methoxyethyl group, an ethoxyethyl group, andthe like.

Specific examples of the alkyloxycarbonyl group for R₁ include amethyloxycarbonyl group, an ethyloxycarbonyl group, ann-propyloxycarbonyl group, an iso-propyloxycarbonyl group, and the like.

Specific examples of the alkylcarbonyl group for R₁ include amethylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group,an iso-propylcarbonyl group, an n-butylcarbonyl group, aniso-butylcarbonyl group, a sec-butylcarbonyl group, a tert-butylcarbonylgroup, an n-pentylcarbonyl group, an n-hexylcarbonyl group, and thelike.

Specific examples of the alkenylcarbonyl group for R₁ include avinylcarbonyl group, a 1-methylvinylcarbonyl group, and the like.

Specific examples of the cycloalkylcarbonyl group for R₁ include acyclopropylcarbonyl group, a cyclobutylcarbonyl group, acyclopentylcarbonyl group, a cyclohexylcarbonyl group, and the like.

Specific examples of the benzoyl group substituted by alkyl group(s) forR₁ include a 2-methylbenzoyl group, a 3-methylbenzoyl group, a4-methylbenzoyl group, a 4-tert-butylbenzoyl group, and the like.

Specific examples of the benzoyl group substituted by halogen atom(s)for R₁ include a 2-chlorobenzoyl group, a 3-chlorobenzoyl group, a4-chlorobenzoyl group, a 3,4-dichloro-benzoyl group, a 4-fluorobenzoylgroup, and the like.

Although R₁ can take various substituents as described above, it ispreferably a hydrogen atom, an alkylcarbonyl group having from 1 to 4carbon atoms or a cyclopropylcarbonyl group.

Specific examples of the alkylamino group for R₂ include a methylaminogroup, an ethylamino group, an n-propyl-amino group, an iso-propylaminogroup, an n-butylamino group, an iso-butylamino group, a sec-butylaminogroup, a tert-butylamino group, an n-pentylamino group, and the like,preferably a methylamino group.

Specific examples of the di-substituted alkylamino group for R₂ includea dimethylamino group, a diethylamino group, an N-methyl-N-ethylaminogroup, an N-methyl-N-n-propylamino group, an N-methyl-N-n-butylaminogroup, and the like, preferably a dimethylamino group.

Specific examples of the alkenylamino group for R₂ include a1-propenylamino group, a 2-propenylamino group, and the like.

Specific examples of the alkynylamino group for R₂ include apropargylamino group, and the like.

Specific examples of the alkoxyalkylamino group for R₂ include amethoxymethylamino group, an ethoxymethylamino group, ann-propoxymethylamino group, an iso-propoxymethylamino group, amethoxyethylamino group, an ethoxyethylamino group, and the like.

Specific examples of the alkyloxycarbonyl group denoted by Y₁ for R₂include a methyloxycarbonyl group, an ethyloxy-carbonyl group, ann-propyloxycarbonyl group, an iso-propyloxy-carbonyl group, and thelike.

Specific examples of the alkylcarbonyl group denoted by Y₁ for R₂include a methylcarbonyl group, an ethylcarbonyl group, ann-propylcarbonyl group, an iso-propylcarbonyl group, an n-butylcarbonylgroup, an isobutylcarbonyl group, a sec-butyl-carbonyl group, atertbutylcarbonyl group, an n-pentylcarbonyl group, an n-hexylcarbonylgroup, and the like, preferably a methylcarbonyl group, an ethylcarbonylgroup, an n-propylcarbonyl group, an iso-propylcarbonyl group, ann-butylcarbonyl group, an iso-butylcarbonyl group, a sec-butylcarbonylgroup and a tert-butylcarbonyl group.

Specific examples of the alkenylcarbonyl group denoted by Y₁ for R₂include a vinylcarbonyl group, a 1-methyl-vinylcarbonyl group, and thelike.

Specific examples of the cycloalkylcarbonyl group denoted by Y₁ for R₂include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, acyclopentylcarbonyl group, a cyclo-hexylcarbonyl group, and the like,preferably a cyclopropyl-carbonyl group.

Specific examples of the benzoyl group substituted byalkyl group(s)denoted by Y₁ for R₂ include a 2-methylbenzoyl group, a 3-methylbenzoylgroup, a 4-methylbenzoyl group, a 4-tert-butylbenzoyl group, and thelike.

Specific examples of the benzoyl group substituted by halogen atom(s)denoted by Y₁ for R₂ include a 2-chlorobenzoyl group, a 3-chlorobenzoylgroup, a 4-chlorobenzoyl group, a 3,4-dichlorobenzoyl group, a 4-fluorobenzoyl group, and the like.

Specific examples of the alkyl group denoted by Y₂ for R₂ include amethyl group, an ethyl group, an n-propyl group, an iso-propyl group, ann-butyl group, an iso-butyl group, a sec-butyl group, a tert-butylgroup, an n-pentyl group, and the like, preferably a methyl group.

In the formula (1), compounds in which R₁ and Y₁ are concurrently analkylcarbonyl group having from 1 to 4 carbon atoms or acyclopropylcarbonyl group are preferred from the viewpoint of bothinsecticidal activity and production method.

In the development of a formulation for use on animals, there areseveral parameters that must be considered. These are:

(a) Concentration high enough to minimize the volume of the topicalformulation applied to the animal (one would not want to put 20 ml,e.g., onto a small cat).

(b) The formulation should be stable at 130° F., at 40° F. and in the−10° F. to 0° F. range. This is required to help ensure that theformulation remains stable under the conditions that it could meet incommerce.

(c) Safe to use on the animal—particularly non-irritating since theproduct is applied to the skin. Also safe if ingested by the animal;ingestion can occur when cats groom themselves.

(d) Safe to use by the consumer.

(e) Efficacious in use—should kill greater than 90% of the fleas up to28 days.

(f) Efficacy would be reduced if crystallization occurred in thepackage.

(g) Needs to be aesthetically pleasing—“no oily drop” on the animal whenapplied.

(h) Fast drying to reduce the chance of the animal shaking off theliquid thereby reducing efficacy.

(i) Microbiologically stable.

The above-referenced patents recognize different possible solvents, butdo not provide information on how to formulate the insecticide in anon-irritating manner. No examples were given in which the compoundswere used on animals. Additionally, in all of the examples given thecompounds were dissolved into solvents that are undesirable to use onanimals. Specifically, acetone, used in all but one of the examples, isvery irritating by both inhalation and skin contact, due to de-fattingaction on skin and mucous membranes. It is also very irritating to theeyes. Accordingly, there is a need to develop a different solvent forthese compounds that can be used on animals. The present formulationsatisfies the parameters detailed above.

The following examples are given for purposes of illustration only andare not intended to be construed in a limiting manner.

EXAMPLE 1 Preparation of1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine (dinotefuran)

A mixture comprising 10.0 g of (tetrahydro-3-furanyl)methanol, 29.5 g oftrifluoromethanesulfonic anhydride, 10.0 g of pyridine and 200 ml ofdichloromethane was stirred for an hour at room temperature. Water waspoured into the reaction solution to separate the organic layer, whichwas washed with 1 N hydrochloric acid, water and a saturated salinesolution, dried, and concentrated to obtain 20 g of3-tetrahydro-furanylmethyl triflate. 3.25 g of 60% sodium hydride wereadded to 12.5 g of 1,5-dimethyl-2-nitroiminohexahydro-1,3,5-triazine and60 ml of DMF at room temperature, followed by stirring for an hour. 20.0g of the 3-tetrahydrofuranylmethyl triflate were added thereto, and themixture was stirred at 50° C. for 2 hours. After cooling the mixture toroom temperature, 50 ml of 2N hydrochloric acid were added thereto,followed by stirring at 50° C. for 2 hours. The resultant mixture wasneutralized with sodium bicarbonate and extracted with dichloromethane,and the extract was dried and concentrated. The residue thus obtainedwas purified by silica gel column chromatography (eluent: ethylacetate/hexane=1/1) to obtain 7.8 g of1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine(dinotefuran).

EXAMPLE 2 Preparation of Insecticide Formulation

5 g (i.e., 5.6% (weight/weight)) of dinotefuran was dissolved into 100ml of a mixture comprising 70% ethanol and 30% water. The resultingmixture can be spot applied to companion animals, such as dogs and catsand will kill fleas, ticks and other insects.

EXAMPLE 3 In Vivo Activity of a Flea Dermal Treatment Against the CatFlea (Ctenocephalides felis) on Cats

Eighteen cats were separated into three groups each containing 6 cats.Group 1 (6 cats each weighing 9 lbs. or less) remained untreated asNon-Treated Controls. Group 2 (6 cats each over 9 lbs.) were treatedwith 3.4 ml of the dinotefuran insecticide formulation (5.71% w/w).Group 3 (6 cats each weighing 9 lbs. or less) were treated with 1.5 mlof the dinotefuran insecticide formulation (5.71% w/w).

Approximately 18 hours prior to treatment the cats were infested with100 cat fleas (Ctenocephalides felis) which were applied to the animal'sback. Cats in Groups 2 and 3 were then treated with the indicated volumeof insecticide by dispensing the liquid at skin level between theshoulder blades. Flea counts were taken at day 1 (i.e., 24 hourspost-treatment), day 8, day 15, day 22 and day 29. Cats were re-infestedwith 100 fleas on days 7, 14, 21, and 28. To determine the efficacy ofthe dermal treatment, the number of fleas found on treated cats wascompared to the number of fleas found on untreated cats. Percentreduction was determined as follows and the results are summarized inTable 1: $\frac{\begin{matrix}{{{Mean}\quad {Number}\quad {of}\quad {fleas}\quad {on}\quad {Untreated}\quad {Cats}} -} \\{{Mean}\quad {Number}\quad {of}\quad {fleas}\quad {on}\quad {Treated}\quad {Cats}}\end{matrix}}{{Mean}\quad {Number}\quad {of}\quad {fleas}\quad {on}\quad {Untreated}\quad {Cats}} \times 100\%$

As shown in Table 1 the results demonstrate that the dosages used onGroups 2 and 3 are both effective at reducing the number of adult fleason cats through at least 29 days and thus are effective as a one monthdermal treatment.

TABLE 1 Controlled Percent Reduction in Flea Population Day 1 Day 8 Day15 Day 22 Day 29 Control 0 0 0 0 0 Group 1 Group 2 100 100 99 99 96Group 3 100 98 95 95 91

It will thus be seen that the objects set forth above, among those madeapparent from the preceding description, are efficiently attained and,since certain changes may be made in carrying out the above method andin the composition set forth without departing from the spirit and scopeof the invention, it is intended that all matter contained in the abovedescription shall be interpreted as illustrative and not in a limitingsense.

It is also understood that the following claims are intended to coverall of the generic and specific features of the invention hereindescribed and all statements of the scope of the invention which, as amatter of language, might be said to fall therebetween.

Particularly it is to be understood that in said claims, ingredients orcompounds recited in the singular are intended to include compatiblemixtures of such ingredients wherever the sense permits.

What is claimed is:
 1. An insecticide formulation comprising about 4-9% dinotefuran dissolved in a solvent component comprising an ethanol-water combination comprising about 65-75% ethanol, wherein said formulation is non-irritating to the skin of dogs and cats.
 2. The insecticide of claim 1, wherein said solvent component further comprises isopropanol.
 3. The insecticide of claim 1, wherein said dinotefuran is dissolved in the formulation to a concentration of about 5-8%.
 4. The insecticide of claim claim 1, wherein the ethanol-water combination is about 69-71% ethanol.
 5. A method of controlling insect infestation in animals, comprising dissolving about 4-9% dinotefuran in a solvent component comprising water and about 65-75% ethanol and applying an insecticidably effective amount of the solution to an animal, wherein the solution is not irritating to animals.
 6. The method of claim 5, wherein the animal is a cat or a dog.
 7. The method of claim 5, wherein the insect killed is a flea.
 8. The method of claim 5, wherein the solvent component comprises 25-44% ethanol and 25-45% isopropanol.
 9. The method of claim 5, wherein the solvent component comprises 30-35% ethanol and 30-35% DPM.
 10. An insecticide formulation comprising about 4-9% dinotefuran dissolved in a solvent component comprising a dipropyleneglycol monomethylether (DPM)-water combination comprising about 25-55% DPM, wherein said formulation is non-irritating to the skin of dogs and cats.
 11. The insecticide of claim 10, wherein the solvent component comprises 25-40% ethanol, 25-40% DPM and water. 